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Abstract

Cardiac remodeling shows strong sex-based differences. We now characterise the timeline of adverse cardiac remodeling specifically in type 2 diabetes (T2DM), and test the hypothesis that female sex exhibits protection against diabetic cardiomyopathy, in db/db mice. Progressive increases in cardiomyocyte width (on H&E stained ventricular sections) and collagen deposition (on picrosirius red stained sections) are evident in male and female db/db mice at 10, 14 and 18-wks of age compared to their 18-wk nondiabetic db/+ counterparts (n=11 mice/age and gender group, except n=7 female db/+). Diabetes-induced changes in myocardial morphology are all significantly different to same sex db/+ mice on two-way ANOVA. Although females exhibit variance, there are no significant sex differences within each age-group in diabetic mice on post-hoc analysis. Further, the smaller female heart weights in non-diabetic female compared to male mice (P<0.0001) are absent in diabetic mice. Progression of cardiomyocyte hypertrophy and cardiac fibrosis mirrors the time-course of T2DM (hyperglycemia, glycated hemoglobin GHB). Myocardial gene expression of both hypertrophic (β-myosin heavy chain) and fibrotic (pro-collagen III, both on real-time PCR) also increase in db/db mice with age. Interestingly, in contrast to our hypothesis, no sex differences in any of these markers are apparent. Given that serum lipid peroxidation is elevated 1.99±0.16-fold in db/db mice at 18-wks of age, oxidative stress is associated with abnormalities in myocardial structure in this model. In conclusion, we demonstrate that the development of cardiac remodeling in db/db T2DM mice is progressive with age, and parallels impaired glucose metabolism. Surprisingly however, in contrast to other settings of cardiomyopathy, there is no evidence of gender protection in female mice. These findings thus have implications for treatment of cardiac complications in T2DM in clinical settings.